Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

Abstract

Leukemia relapse and chronic graft-versus-host disease (cGVHD) are still major obstacles of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The numbers and activity of natural killer (NK) and Tregulatory cells can be increased post-transplantation by exposure to interleukin-2 (IL-2). We tested whether administering low-dose IL-2 would decrease leukemia relapse while reducing cGVHD after allotransplantation. This controlled, open-label randomized trial included 90 recipients of allotransplants. Subjects were randomized in a 1:1 ratio to either receive or not receive low-dose IL-2 during the early post-transplantation period. Patients in the IL-2 arm received a subcutaneous injection of low-dose IL-2 (1£10 6 U/d) on day 60 after allo-HSCT. IL-2 was administered daily for 14 d followed by a 14-d hiatus. The primary endpoint was the cumulative incidence of leukemia relapse (CIR). Three-year CIRs for the IL-2 arm and control arm were 23% (range 16-30%) and 11% (range 6-15%; p D 0.20), respectively. Minimal residual disease-positive (MRDC) tests were more common in the IL-2 arm compared to the control arm (36% [range 29-44%] vs. 15% [range 10-20%], p D 0.03). The cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was lower in the IL-2 arm compared to the control arm (33% [range 26-39%] vs. 57% [range 49-64%), p D 0.02). Therefore, the 3-y GVHD-free and GVHD progression-free survival (GPFS) rates were significantly higher in the IL-2 arm compared to the control arm (47% [range 39-55%] vs. 31% [range 25-38%], p D 0.048). Blood Tregs, NK cells, and NK-cell cytotoxicity were increased in subjects in the IL-2 arm between 3 mo and 6 mo post-transplantation. Administration of low-dose IL-2 during the immediate post-transplantation period was associated with a higher GPFS but did not decrease the CIR.

Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases

“…Alleviation of the manifestations of chronic GVHD was observed in a substantial proportion of these patients; out of 23 patients, 12 had major responses involving multiple sites (15). Further studies proposed similar regimens for the prevention of GVHD [e.g., s.c. injections of low-dose IL-2 (1 million IU/m 2 ) daily for 14 d, followed by a 14-d hiatus (37), or 0.1-0.2 million IU/m 2 three times per week for days 0-90 (38)]. These findings suggested that the prophylactic administration of lowdose IL-2 could effectively enhance early Treg expansion and suppress acute and chronic GVHD (35,36).…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…297,309,310 Accumulating evidence suggest indeed that metronomic chemotherapy and hypofractionated radiation (rather than chemotherapy at the MTD and high single-dose radiation) exerts superior immunostimulatory (and hence therapeutic, at least in some settings) effects. [311][312][313][314] Alongside, it will be important to devise highly efficient combinatorial regimens that harness not only the ability of some treatments to drive ICD, but also the off-target immunostimulatory effects of a variety of agents.…”

The promise of CD4+FoxP3+ regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation

“…Correlative studies demonstrated that circulating Treg and natural killer (NK) cells were increased in the IL-2 cohort during the treatment periods. 76…”